Table 1 Clinical experimental study of targeted therapy combined with chemotherapy

NSABP B-31 and NCCTG N9831 [25]

doxorubicin + cyclophosphamide + paclitaxel (DCP) vs. doxorubicin + cyclophosphamide + paclitaxel + trastuzumab (DCPT)

HER2-positive operable breast cancer, (ER or PR-positive: n = 2115/4046, 52%)

DCPT led to a 37% relative improvement in OS (p < 0.001) and an increase in 10-year OS rate from 75.2–84%.; in 10-year DFS rate from 62.2–73.7%.

NOAH [26]

Chemotherapy (C) vs. chemotherapy + trastuzumab (TC)

HER2-positive locally advanced or inflammatory breast cancer, (HR-positive: n = 84/235, 36%)

C vs. TC in the 3-year event-free survival was 56% vs. 71%

M77001 [27]

trastuzumab + docetaxel (TD) vs. docetaxel (D)

HER2–positive metastatic breast cancer, (HR-positive: n = 91/186, 49%)

TD vs. D in terms of overall response rate was 61% v 34%; median OS was 31.2 v 22.7 months; median time to disease progression was 11.7 v 6.1 months; median time to treatment failure was 9.8 v 5.3 months.

APHINITY [28]

pertuzumab + chemotherapy + trastuzumab vs. placebo + chemotherapy + trastuzumab

node-positive HER2-positive early BC, (HR-positive: n = 3082/4805, 64%)

pertuzumab vs. placebo groups:6-year iDFS being 88% vs. 83%.

NeoSphere [29]

pertuzumab + trastuzumab + docetaxel (PTD) vs. trastuzumab + docetaxel (TD)

locally advanced, inflammatory, or early-stage HER2-positive breast cancer, (HR-positive: n = 197/417, 47%)

pCR 85% in PTD vs. 76% in TD.

CLEOPATRA [30]

pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel

HER2–positive metastatic breast cancer, (HR-positive: n = 388/808, 48%)

placebo versus pertuzumab arm in terms of median PFS of 12·4 vs. 18·7 months; the risk of death in the pertuzumab group was reduced by 34%.

EGF100151 [38]

lapatinib + capecitabine (LC) vs. capecitabine(C)

HER2-positive MBC female patients who have received treatment, (ER or PR-positive: n = 192/408, 47%)

LC vs. C in terms of median OS times were 75.0 v 64.7 weeks.

NCT00281658 [39]

lapatinib + paclitaxel (LP) vs. placebo + paclitaxel (P)

HER2-overexpressing metastatic breast cancer, (ER or PR-positive: n = 224/444, 50%)

LP vs. P in terms of median OS was 27.8 v 20.5 months; median PFS was 9.7 v 6.5 months; ORR was 69% v 50%.

ExteNET [42]

Neratinib vs. Placebo

After trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer, (HR-positive: n = 1631/2840, 57%)

Neratinib vs. Placebo of the 5-year invasive disease-free survival was 90·2% vs. 87·7%.

NALA [43]

neratinib + capecitabine (NC) vs. lapatinib + capecitabine (LC)

HER2-positive, metastatic breast cancer with ≥ 2 previous HER2-directed MBC regimens, (HR-positive: n = 367/621, 59%)

NC vs. LC in terms of ORRs was 32.8% vs. 26.7%; median DoR was 8.5 vs. 5.6 months; diarrhea 83% v 66%; and nausea 53% v 42%.

PHOEBE [44]

pyrotinib + capecitabine (PC) vs. lapatinib + capecitabine (LC)

HER2-positive metastatic breast cancer, (ER or PR-positive: n = 120/267, 45%)

PC vs. LC in terms of median PFS was12·5 months vs. 6·8 months.

HER2CLIMB [45]

tucatinib + trastuzumab + capecitabine (TTC) vs. placebo + trastuzumab + capecitabine (PTC)

HER2–positive breast cancer with brain metastases, (HR-positive: n = 166/291, 57%)

In the TTC, the risk of intracranial progression or death was reduced by 68%; the risk of death was lowered by 42%. TTC vs. PTC in terms of median PFS was 9.9 versus 4.2 months; median OS was 18.1 vs. 12.0 months; ORR was 47.3% vs. 20.0%.

EMILIA [47]

T-DM1 vs. lapatinib + capecitabine (LC)

HER2-positive advanced breast cancer, (HR-positive: n = 545/991, 55%)

T vs. LC in terms of median PFS was 9.6 vs. 6.4 months; median OS was 30.9 vs. 25.1 months; ORR was 43.6% vs. 30.8%; Rates of adverse events of grade 3 or above was LC vs. T (57% vs. 41%).

KATHERINE [48]

T-DM1 vs. trastuzumab

HER2-positive early breast cancer after receiving neoadjuvant therapy, (HR-positive: n = 1074/1486, 72%)

The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 vs. 77.0% in the trastuzumab.

DESTINY-Breast01 [49]

Trastuzumab deruxtecan (T-DXd)

HER2-positive metastatic breast cancer who had received previous treatment with T-DM1, (HR-positive: n = 97/184, 53%)

The median duration of follow-up was 11.1 months; the median response duration was 14.8 months; and the median PFS was 16.4 months.

DESTINY-Breast02 [50]

T-DXd vs. capecitabine + trastuzumab or capecitabine + lapatinib (TC/LC)

HER2-positive metastatic breast cancer who were refractory or resistant to T-DM1, (HR-positive: n = 356/608, 59%)

T-DXd vs. TC/LC in the median follow-up was 21·5 months vs. 18·6 months; median PFS was 17·8 months versus 6·9 months; median OS 39 vs. 26.5 months; ORR was 69.7% vs. 29.2%.

DESTINY-Breast03 [51]

T-DXd vs. T-DM1

HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, (HR-positive: n = 265/524, 51%)

T-DXd vs. T-DM1 of those who were alive without disease progression at 12 months was 75.8% vs34.1%; patients who were of alive at 12 months was 94.1% vs. 85.9%; an overall response was 79.7% vs. 34.2%.

DESTINY-Breast04 [53]

T-DXd vs. chemotherapy

HR positive and negative HER2 low expression in patients with advanced breast cancer, (HR-positive: n = 490/557, 88%)

In the HR–positive cohort, T-DXd vs. C in terms of median PFS was 10.1 vs. 5.4 months; OS was 23.9 vs. 17.5 months. Among all patients, T-DXd vs. C in terms of median PFS was 9.9 vs. 5.1 months; OS was 23.4 vs. 16.8 months.

RAD001 [61]

trastuzumab + everolimus

HER2-overexpressing metastatic breast cancer, (ER or PR-positive: n = 28/47, 60%)

everolimus + trastuzumab resulting in a clinical benefit rate of 34%, the median PFS was 4.1 month.